小柯机器人

原发性免疫缺陷人群的全基因组测序
2020-05-07 13:08

英国剑桥大学Paul A. Lyons和James E. D. Thaventhiran研究团队合作取得新进展。他们进行了零星的原发性免疫缺陷人群的全基因组测序。2020年5月6日的《自然》杂志发表了这一成果。

他们通过在1,318名参与者的大型原发性免疫缺陷(PID)研究中运用全基因组测序来解决一些挑战。对886例PID病例的基因组编码区进行分析发现,这些基因中涉及单基因PID的已知基因的致病突变发生在10.3%的患者中,并且贝叶斯方法(BeviMed4)确定了多个新的候选PID -相关基因,包括IVNS1ABP。

他们还分析了非编码基因组,发现调节区的缺失是疾病发生的原因。此外,他们使用了全基因组关联研究来鉴定与PID相关的基因座,并找到了新的高渗透性单基因变异体和常见变异体(在PTPN2和SOCS1基因座上)共定位以及相互作用的证据。这解释了常见变异体对PID中观察到的可变渗透率和表型复杂性的贡献。因此,在PID的诊断中使用基于研究的全基因组测序方法可以提高诊断率,并进一步使人们了解影响人类免疫应答的关键途径。

据了解,PID的特征是易复发且导致感染甚至威胁生命,造成自身免疫和癌症,并且构成主要的诊断和治疗挑战。尽管最严重的PID形式是在儿童早期就发现的,但大多数患者是成年后出现的,通常没有明显的家族史,并且临床表型具有广泛的免疫失调的特征。大约25%的患者患有自身免疫性疾病,过敏现象普遍存在,并且高达10%发生淋巴样恶性肿瘤。因此,在散发性(或非家族性)PID中,遗传诊断很困难,并且遗传学的作用尚不明确。

附:英文原文

Title: Whole-genome sequencing of a sporadic primary immunodeficiency cohort

Author: James E. D. Thaventhiran, Hana Lango Allen, Oliver S. Burren, William Rae, Daniel Greene, Emily Staples, Zinan Zhang, James H. R. Farmery, Ilenia Simeoni, Elizabeth Rivers, Jesmeen Maimaris, Christopher J. Penkett, Jonathan Stephens, Sri V. V. Deevi, Alba Sanchis-Juan, Nicholas S. Gleadall, Moira J. Thomas, Ravishankar B. Sargur, Pavels Gordins, Helen E. Baxendale, Matthew Brown, Paul Tuijnenburg, Austen Worth, Steven Hanson, Rachel J. Linger, Matthew S. Buckland, Paula J. Rayner-Matthews, Kimberly C. Gilmour, Crina Samarghitean, Suranjith L. Seneviratne, David M. Sansom, Andy G. Lynch, Karyn Megy, Eva Ellinghaus, David Ellinghaus, Silje F. Jorgensen, Tom H. Karlsen, Kathleen E. Stirrups, Antony J. Cutler, Dinakantha S. Kumararatne, Anita Chandra, J. David M. Edgar, Archana Herwadkar, Nichola Cooper, Sofia Grigoriadou, Aarnoud P. Huissoon, Sarah Goddard, Stephen Jolles, Catharina Schuetz, Felix Boschann, Paul A. Lyons

Issue&Volume: 2020-05-06

Abstract: Primary immunodeficiency (PID) is characterized by recurrent and often life-threatening infections, autoimmunity and cancer, and it poses major diagnostic and therapeutic challenges. Although the most severe forms of PID are identified in early childhood, most patients present in adulthood, typically with no apparent family history and a variable clinical phenotype of widespread immune dysregulation: about 25% of patients have autoimmune disease, allergy is prevalent and up to 10% develop lymphoid malignancies1,2,3. Consequently, in sporadic (or non-familial) PID genetic diagnosis is difficult and the role of genetics is not well defined. Here we address these challenges by performing whole-genome sequencing in a large PID cohort of 1,318 participants. An analysis of the coding regions of the genome in 886 index cases of PID found that disease-causing mutations in known genes that are implicated in monogenic PID occurred in 10.3% of these patients, and a Bayesian approach (BeviMed4) identified multiple new candidate PID-associated genes, including IVNS1ABP. We also examined the noncoding genome, and found deletions in regulatory regions that contribute to disease causation. In addition, we used a genome-wide association study to identify loci that are associated with PID, and found evidence for the colocalization of—and interplay between—novel high-penetrance monogenic variants and common variants (at the PTPN2 and SOCS1 loci). This begins to explain the contribution of common variants to the variable penetrance and phenotypic complexity that are observed in PID. Thus, using a cohort-based whole-genome-sequencing approach in the diagnosis of PID can increase diagnostic yield and further our understanding of the key pathways that influence immune responsiveness in humans.

DOI: 10.1038/s41586-020-2265-1

Source: https://www.nature.com/articles/s41586-020-2265-1

Nature:《自然》,创刊于1869年。隶属于施普林格·自然出版集团,最新IF:69.504
官方网址:http://www.nature.com/
投稿链接:http://www.nature.com/authors/submit_manuscript.html


本期文章:《自然》:Online/在线发表

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